This invention relates to substituted 4-oxy-pyridines and more specifically to such compounds that bind to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases.
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits. Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636.
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York).
Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
Certain 4-oxyquinoline derivatives have been described as being useful as anxiolytics, hpnotics, anticonvulsants, and antiepileptics. See, for example, European Patent Applications EP 362006 and EP 205375.
This invention provides substituted 4-oxy-pyridine derivatives that bind to the benzodiazepine site of the GABAA receptor, including human GABAA receptors.
Thus, the invention provides compounds of Formula I and Formula II (shown below), and pharmaceutical compositions comprising compounds of Formula I and Formula II.
The invention further comprises methods of treating patients suffering from CNS disorders with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with a therapeutically effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue sections.
Accordingly, in a broad aspect, the invention provides compounds of Formula I: 
and the pharmaceutically acceptable salts thereof, wherein: 
represents: 
wherein:
A, B, C, and D are independently nitrogen or CR1, and
E represents oxygen, sulfur or NR2,
wherein
when Ar is a 6-membered ring, 1 or 2 of A, B, C, and D are nitrogen; and
when Ar is a 5-membered ring, C and D are both CR1 and E is nitrogen, sulfur, or NR2,
where
R1, at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, C1-6 alkyl, amino, mono and di(C1-6)alkylamino, and C1-6 alkoxy; and
R2 is selected from the group consisting of hydrogen, halogen, cyano, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy, C1-6 alkyl, amino, and mono or di(C1-C6)alkylamino;
W is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each of which is unsubstituted or substituted with one or more R3; and
Q is selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, wherein each is unsubstituted or substituted with one or more of R4;
R3 and R4 at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94OR6, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NHR6, xe2x80x94SO2N(R6)2, amino, xe2x80x94NHR6, xe2x80x94N(R6)2, xe2x80x94N(R6)CO(R6), xe2x80x94N(R6)CO2(R6), xe2x80x94CONH2, xe2x80x94CONH(R6), xe2x80x94CON(R6)2, xe2x80x94CO2(R6), xe2x80x94S(R6), SO(R6), xe2x80x94SO2(R6), and R7, wherein
R6, at each occurrence, is independently selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, and C5-9 cycloalkynyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, amino, C1-8 alkoxy, and C1-8 alkyl,
R7 at each occurrence is independently selected from the group consisting of C1-8 alkyl, C1-8 alkenyl, C1-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, and C5-9 cycloalkynyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, xe2x80x94OR6, C1-6alkyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NHR6, xe2x80x94SO2N(R6)2, amino, xe2x80x94NHR6, xe2x80x94N(R6)2, xe2x80x94N(R6)CO(R6), xe2x80x94N(R6)CO2(R6), xe2x80x94CONH2, xe2x80x94CONH(R6), xe2x80x94CON(R6)2, xe2x80x94CO2H, xe2x80x94CO2(R6), xe2x80x94S(R6), xe2x80x94SO(R6), xe2x80x94SO2(R6), and NRaRb, wherein
each NRaRb independently forms a monocyclic or bicyclic ring each of which may contain one or more double bonds, or one or more of oxo, O, S, SO, SO2, NH, or N(R2) , wherein R2 is defined above and independently selected at each occurrence; or
Q is a group of the formula NR8R9 wherein
R8 and R9 are independently hydrogen or R7; or
R8, R9 and the nitrogen to which they are attached form a heterocycloalkyl ring having from 5 to 8 ring atoms and where 1 or 2 of the ring atoms are selected from N, S, and O, with remaining ring members being carbon, CH, or CH2, which heteroacycloalkyl ring is unsubstituted or substituted with one or more independently selected R4 groups; and
X is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)n(Cxe2x95x90O)xe2x80x94, wherein each n is independently 1, 2, or 3.
The invention also provides compounds of Formula II 
and the pharmaceutically acceptable salts thereof, wherein:
W, Q, n, and each R1 are as defined for Formula I, above.
In another aspect, the invention provides intermediates useful for preparing the compounds of Formulas I and II.
In a further aspect, the invention provides methods for making compounds of Formula I and II.